From June 3 to June 19, 2008, the U.S. Food and Drug Administration (FDA) conducted an inspection of your PET production facility located at 630 West 168th Street, New York, NY. The inspection revealed significant deviations from the United States Pharmacopoeia (USP) compounding standards and official monograph for Positron Emission Tomography (PET) drugs in the manufacturing of your PET drugs (i.e., Fludeoxyglucose (FDG) F18 Injection, Ammonia N13 Injection, Water O15 Injection, and Oxygen 015 Gas). These deviations were listed on an Inspectional Observations (FDA-483) form issued to you at the close of the inspection. These deviations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(C) [21 U.S.C. § 351(a)(2)(C)] of the. Federal Food, Drug, and Cosmetic Act (the Act).

We also have completed review of your August 18, 2008 response to the Form FDA-483 observations. The deficiencies need more comprehensive corrections than the actions you have proposed or taken, especially since many of these are repeat violations.

The inspection revealed that your Quality, Production, Laboratory, and Facilities and Equipment systems employed during the manufacture and processing of drug products are not in conformity with the USP compounding standards and official monograph for PET drugs.

The deviations observed during the inspection include, but are not limited to the following:

1. You failed to a) investigate unacceptable quality control test results, b) document the outcome of such investigations, and c) follow written procedures. This is a repeat violation from the 2004 inspection.

a. You failed to thoroughly investigate an out-of-specification (OOS) result for sterility involving FDG drug product (lot F051508-1). Your personnel did not identify the cause of the failure, immediately send out the implicated culture tube for microbial identification (as per SOP No. Q19 (b)(4) implement corrections, and provide documentation of the outcome of the investigation. In addition, the product was retested without demonstrating that the first test was invalid. The lot was then released.

We acknowledge your response which includes identification of the isolate and an investigation which concluded "No patients were found to have evidence of infection related to this batch." However, we find that your response is not fully adequate because it does not include corrections to prevent similar occurrences. In addition, your procedure SOP No. Q19 should be revised to ensure that retesting complies with the criteria as described in the USP.

b. For the Residual Solvents test (FDG, lot F052208-1) by Gas Chromatography (GC), the system suitability test failed to meet the verification standard specification (used to confirm that the standard was prepared correctly). The product was released despite this failure, and no investigation was conducted.

Your response is inadequate. Please investigate this failure, include corrections to prevent similar incidents from occurring, and conduct an impact assessment to determine the extent of the system suitability failure on the test results.

2. You failed to reject a batch of PET radiopharmaceutical that did not meet specifications, maintain a written record that includes raw analytical data on each batch of compounded PET radiopharmaceutical, and perform verification studies for revised compounding procedures. Specifically, regarding FDG injection, batch F072607-1:

a. A batch of "compounded FDG injection failed the residual solvent specification for acetonitrile (ACN). You failed to maintain a written record that includes the raw analytical data such as the chromatograms and results showing the high levels of ACN that was originally found. This is a repeat violation from the 2004 inspection.

b. You failed to reject the batch of FDG injection upon determining the level of ACN exceeded the established limit of 0.04%.

c. Your personnel made a change by diluting the failed product with (b)(4) in order to meet the ACN specification. The product was released without the correct stabilizer (i.e., (b)(4) was accidentally substituted for (b)(4) and without conducting verification studies for these changes (e.g., chemical and microbiological testing). This is a repeat violation from the 2004 inspection.

3. You failed to conduct quality control testing on batches of PET radiopharmaceuticals according to written procedures. You did not ensure that the minimum standards, as specified in the corresponding USP monograph, are followed to ensure each batch or sub-batch of PET radiopharmaceuticals meets the acceptance cri teria for identity, purity, and quality. For example,

a. The Residual Solvents test for FDG Injection (lots F041008-01 and F070907-01) was not performed. This is a repeat violation from the 2004 inspection.

b. The Heavy Metals test, required by the master batch record, is not performed for Water Ol5 injection.

We acknowledge your commitment to perform the Heavy Metals test annually. The response states in part that the frequency of testing is justified because the size/volume of your batches is not sufficient for sampling to perform the test for each sub-batch. Please provide information that supports your justification (e.g. number of sub-batches per year). In addition, provide data derived from the manufacturing process validation studies (i.e., verification studies) and/or in-process controls to support your proposed frequency of testing.

4. You failed to ensure that the quality of the sub-batches of PET drugs (with a half-life of less than 20 minutes) administered to patients is acceptable. You failed to conduct verification testing in the initial and final sub-batches in accordance with your procedures and the USP. A review of Ammonia N13 injection batch records revealed that the portion of the batch record that should include the results for the final QC sub batch is left blank.

5. You failed to establish appropriate sterility test procedures and to conduct testing appropriately. For example,

a. The (b)(4) used for detection of anaerobic organisms was not suitable for use. Observation of multiple lots of FDG Injection (e.g. F053008-01, F05290801, F052808-01) in FTM tubes undergoing sterility testing showed that the media failed the color indicator requirement, indicative of an excess amount of oxygen. Consequently, the sterility test has been ineffective in detecting spore-forming anaerobic microorganisms.

b. The sterility test for FDG drug product (lot F051508-1) was not performed within twenty-four hours after compounding, and your procedure does not include a provision to ensure this timeframe is consistently met.

6. You failed to establish appropriate test procedures and to conduct testing appropriately for the performance of bacterial endotoxin tests (BET) for your finished product. Your laboratory personnel failed to update the test procedure used for preparing positive endotoxin controls (i.e., (b)(4) to reflect a change in potency (from (b)(4) of a new Control Standard Endotoxin (CSE) vial, following its substitution in Marc Laboratory personnel adjusted their CSE dilution requirements incorrectly, thus obtaining results that were not accurate and reliable.

We acknowledge your commitment to train the responsible staff. Please ensure that supervisors are included in this training and conduct an impact assessment to determine the extent of the violation (i.e., failure to use the correct CSE and calculations) on the quality of your released batches.

7. The media fill is inadequate in that verification of the media's growth promotion capability in the PET drug container is not performed.

8. Operation of analytical equipment is not checked at suitable intervals, and maintenance is not performed according to appropriate written procedures. Equipment verification testing and maintenance are not routinely performed on the following instruments used for quality control testing of radiopharmaceuticals in the Radiopharmacy Laboratory: (b)(4) TLC scanner (b)(4) Chromatography detector, GC radiation detector, and HPLC (b)(4) detector: This is a repeat violation from the 2004 inspection.

We acknowledge your commitment to include the (b)(4) GC and (b)(4) TLC scanner in your calibration and maintenance program. However, your response did not address the remaining instruments. Please provide corrections to address the violation.

All of the above deficiencies are indicative of your failure to have a designated person(s) to ensure that all activities are carried out and completed properly by qualified and trained personnel. We are concerned about the quality control systems and procedural problems that have allowed these significant deficiencies to occur.

We have additional comments to your August 18, 2008 response as follows:

The response indicates that a reorganization is underway to combine the Radiochemistry and Radiopharmacy Laboratories and to recruit a consultant to review all SOPs and conduct QA/QC auditing of the Radiopharmacy Laboratory. We note that your December 6, 2004 response (from Dr. Harvey R. Colten) to the FDA-483 (issued on November 10, 2004) also indicates that you hired a consultant to assist with your program, yet the FDA inspection discovered deviations (including repeated ones) from the USP compounding standards and official monograph requirements for PET drugs. Please comment on how the use of consultants will ensure that your Quality Management System will identify and correct deficiencies and prevent occurrences.

With respect to Form FDA-483 items 2A, 2B, 6, 7, and 8F (items 5a, 2c, and 3a of this letter) concerning failure to establish controls to demonstrate the suitability of the medium used for sterility testing, failure to reject products failing to meet established specifications, failure to establish verification procedures, and release of batches of FDG injection without the required quality control testing for residual solvents and radionuclidic purity, your response indicates that you will implement a QA/QC procedure on or before September 1, 2008 and that you will notify us when this procedure is implemented. Please provide the procedure and any other corrective actions.

The violations cited in this letter are not intended to be an all-inclusive statement of the violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that you comply with all requirements of the Act.

You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps, other than those already submitted, that you will take, or have taken to correct the violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. If you no longer manufacture or market any of your PET drugs, your response should so indicate, including the reasons that, and the date on which, you ceased production.

Please direct any correspondence to: Food and Drug Administration, Attention: Lillian, C. Aveta, at the above address. If you have any questions, please contact Lillian Aveta at (718) 662-5576.